New tools of toxicology and exposure science opportunities for informing low dose evaluations
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New Tools of Toxicology and Exposure Science: Opportunities for Informing Low-Dose Evaluations. James Bus, PhD, DABT, ATS The Dow Chemical Company “Beyond Science and Decisions: From Problem Formulation to Dose Response” Workshop I, March 16-18, 2010 Austin, Texas.

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New Tools of Toxicology and Exposure Science: Opportunities for Informing Low-Dose Evaluations

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New Tools of Toxicology and Exposure Science: Opportunities for Informing Low-Dose Evaluations

James Bus, PhD, DABT, ATS

The Dow Chemical Company

“Beyond Science and Decisions: From Problem Formulation to Dose Response”

Workshop I, March 16-18, 2010

Austin, Texas


The Paradigm Shift: Low-dose linear response default assumption for cancer and non-cancer endpoints

  • Did Silver Book seriously considered critical alternative, i.e., all responses exhibit practical thresholds (non-linear behaviors)?

  • Evidence of thresholds (non-linear behavior) for all responses:

    • Radiation and chemical hormesis

    • DNA-reactive substances – genotoxicity assays

    • Whole animal cancer and non-cancer bioassays


Assumption of Linearity: The “natural chemicals” conundrum

  • Tens’s of thousands of natural chemicals in everyday environment

    • Many present in significant doses in “healthy foods”

    • Exhibit full range of toxicologic properties associated with anthropogenic chemicals, including genotoxic activity

    • Silver Book default assumption of linear low-dose toxicity responses further magnifies natural chemical conundrum, i.e., otherwise “healthy” foods are judged to be even “unhealthier”

  • Future risk assessment paradigm must be able to differentiate healthy food from true chemical risks

    >>> What can new tools of toxicology and exposure science reveal?


Value of new tools of toxicology: Dose-response

Naciff et.al., Tox.Sci. 2005


Genetic susceptibility

Susceptibility: Dose response implications

PON1 KO?

Wild-type

Response

Dose


*

*

20

MNU

MMS

15

*

Reticulocyte-MN (‰ ave)

10

*

*

5

*

0

0

0.01

0.1

0.5

1

5

10

25

50

Dose group (mkd, 4d)

Nonlinear Dose Response for Micronuclei (MN) in Reticulocytesas Measured by Flow Cytometry


125

100

75

Genes Significantly

Changed vs. Control (#)

50

25

0

0.5

5

50

MMS (mkd, 4d)

Genes Significantly Changed in Liver vs. Control as Measured by Microarray

↝ Agilent complete rat genome(41,121)

↝ GeneSpring prefilter (21,205)

↝ ANOVA p<0.001 (126)↝ Tukey’s post-hoc p<0.05(20 and 121)


Mega-Fish Study: Non-linear Response to Genotoxic Carcinogen Dibenzo[a,l] pyrene

Bailey et.al., Chem.Res.Toxicol. 22: 1264-1276 (2009)


Value of new tools of toxicology: Modes of Action

  • Rapid identification of “alternative” modes of action

    • Liver tumors: PPARα vs CYP P450 enzyme induction

  • Improved animal models, e.g., humanized mice

    • Identify and test potential animal-model-specific responses

  • Test hypothesized “common” and/or “cumulative” modes of action

    • AhR-mediated toxicity

  • Assess question of “how to add” risks of complex mixtures


Exposure-dosimetry relationships: Implications for future risk assessment

  • Advancements in analytical and modeling technologies rapidly improving both animal dosimetry and human exposure evaluations (biomonitoring)

  • Refinements to “Margin of Exposure” approaches

    • “Biomonitoring Equivalents” approach (Hays et.al., Reg.Toxicol.Pharmacol 47: 96-109, 2007)

    • Internal dosimetry for short half-life compounds

      • Steady-state concentrations under conditions of toxicity test

      • Peak and/or steady-state AUCs in human exposures


Linking Animal Toxicity Tests to Human Exposure

From: Hays et.al., Reg.Toxicol.Pharmacol 47: 96-109, 2007


Linking Animal Test Doses to Human Exposure

Saghir et.al., TAAP 211: 245, 2006


Summary

  • New tools of toxicology offer unprecedented opportunities to better characterize the shape of the dose response under dose-exposure conditions relevant to real world exposure

  • Emerging data provides biological basis for existence of toxicological thresholds (non-linearities), even for genotoxic substances

  • Human exposure advances and information can be integrated into dose-response considerations of toxicity tests

    • Opportunities to improve Margin of Exposure risk approaches

  • Objective: Differentiate “healthy” from “harmful”


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